Increased resistance of gram positive pathogens such as Staphylococcus aureus and Enterococcus faecium to conventional antibiotics led to the introduction new class of compounds with good activity. The oxazolidinone have a unique mechanism of action that is different from other antibiotics. The exact mechanism of antibacterial activity of oxazolidinone has not been established, but they appear to exert their inhibitory activity by interfering with an early step in protein synthesis in a generally bacteriostatic manner. Linezolid is the first antibiotic belonging to the new class of oxazolidinone compounds, developed in 1990s and first approved for use in 2000, it is the first commercially available 1,3-oxazolidinone antibiotic possessing excellent antibacterial activity against a wide variety of gram-positive pathogens including those resistant to methicillin and vancomycin. Linezolid is a synthetic oxazolidinone antimicrobial agent chemically designated as (S)—N-({3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide. Linezolid has demonstrated high in vitro antibacterial activity against Mycobacterium tuberculosis and has been used to treat complicated cases of resistant TB in several programmes. While the recommended use of linezolid is restricted to 28 days, with dosage at 600 mg twice daily, drug-resistant TB requires a much longer treatment duration (˜2 years), and therefore, carries an increased risk of adverse effects. This drug suffers from poor pharmacokinetics which led to high dose, i.e., twice daily. Also there are several cases of developing linezolid resistance. By this silicon-switch approach, one can expect to improve pharmacokinetic properties which in turn may reduce the dose of the drug. More importantly, the problem of resistance development can be addressed as there is a structural difference in new sila analogs.
As of 2009, linezolid is the only marketed oxazolidinone, although others are in the process of development. As a protein synthesis inhibitor, it stops the growth of bacteria by disrupting their production of proteins. Linezolid targets ribosomes, inhibits the initiation step of protein synthesis by preventing the formation of functional 70S initiation complex, which is essential to the bacterial translation process and kills bacteria. Linezolid is used for the treatment of vancomycin-resistant Enterococcus faecium, including cases with concurrent bacteremia, treatment of nosocomial pneumonia, complicated and uncomplicated skin and skin structure infections (including diabetic foot infections without concomitant osteomyelitis) and community-acquired pneumonia caused by susceptible strains of specific organisms. Although bacterial resistance to linezolid has remained very low since it was first detected in 1999, however, the world wide reports on development of resistance to linezolid are constantly increasing.
Structurally related PNU-100480 is currently being developed for the treatment of both drug resistant and sensitive tuberculosis (TB).
Another related compound rivaroxaban (BAY 59-7939) is an oxazolidinone derivative optimized for inhibiting both free Factor Xa and Factor Xa bound in the prothrombinase complex. It is a highly selective direct Factor Xa inhibitor with oral bioavailability and rapid onset of action Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban has predictable pharmacokinetics across a wide spectrum of patients.
Therefore, it is necessary to develop an effective alternative belonging to the oxazolidinone group of compounds having activity against a wide variety of gram-positive pathogens including those resistant to methicillin and vancomycin as the oxazolidinones are proved to be effective in inhibiting bacterial translation process than the existing ones. The compounds of the present invention are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as Staphylococci, Streptococci and Enterococci as well as anaerobic organisms such as Bacteroides spp. and Clostridia spp. and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp. The compounds of the present invention are also useful in modulation of coagulation properties of blood-clotting cascade.